The metabolic syndrome of aging, the subject of this Program Project, is most commonly associated with obesity/abdominal adiposity, consists of a constellation of metabolic defects that are important risk factors for age-related diseases. The risks determined by obesity in humans may be mirrored by ad libitum feeding (AL) in animal models. AL models are insulin resistant and have a shorter life span than caloric restricted (CR) models, which also exhibit decreased incidence of age-related illness. Recent evidence has demonstrated that adipose tissue is a very active endocrine organ whose secretory products include hormones, cytokines, and complement factors that might lead to negative biological sequelae. This Project will test if excess nutrients may cause several harmful effects in muscle and adipose tissue, and if a single nutrient sensing pathway, the hexosamine (glvcoprotein) biosynthetic pathway (HBP), can induce these effects, as will be further tested by all components of this Program. In this Project we hypothesize that CR slows aging by preventing the severe chronic metabolic and biological effects that are induced mainly by fat accumulation and nutrient excess. Because insulin resistance is a risk for most human causes of death, we plan to demonstrate the cause-effect relationship between decreased fat and the improvement in insulin action in CR. In addition, we plan to prove that CR animals are protected from nutrient-dependent over-expression of a variety of fat-derived peptides associated with human diseases. We plan to illustrate how over activation of the HBP may induce, both, insulin resistance and the over-expression of fat-derived peptides. Finally we plan to examine the effect of dissociation between fat mass and insulin action in rodents on longevity. This will be achieved by either surgical removal of a biologically important fat depot, improving insulin action by insulin sensitizers, or by a transgenic model that is insulin resistance through activation of a nutrient sensing pathway, but is lean. If all or most of the life-extending benefits of CR can be attributed to decreased fat stores, a special health benefit may be obtained by developing drugs that reduce FM. Moreover, the demonstration of harmful effects of over-expressed adipose-dependent signal/s may lead to the development of pharmacological antagonists that may lead to the modulation of life expectancy.